Our preliminary data suggests that elevated glucose levels block VPF gene induction under hypoxic conditions, thus blunting the normal response to hypoxia. These observations, coupled with clinical observations of the vascular basis of end-organ disease in diabetes lead us to the fundamental hypothesis of this proposal: Interference by elevated glucose levels with the normal homeostatic signals that mediate angiogenesis in a given tissue, ultimately leads to chronic microvascular inadequacy and metabolic injury to these tissues. Thus, the ultimate organ system failure that is observed in chronic diabetes, and in particular the peripheral neuropathy and poor wound healing that results in significant morbidity, may be in part due to hyperglycemic- induced dysfunctional VPF regulation and consequent angiogenic responses. In order to test this hypothesis, we will determine whether elevated glucose levels inhibit hypoxia-and TGFa-induced activation of VPF in skin-derived epithelial and mesenchymal cells. We will further determine whether this inhibition is mediated by inhibition of VPF gene transcription, alterations in mRNA stability, or a combination of both.